For dysfunctional and/or diseased organs or cells of the body, besides therapeutic intervention with drugs, organ or cell transplantation is an alternative, sometimes the last resort in the treatment of the patient. Particularly for patients with leukemia, end-stage renal, cardiac, pulmonary or hepatic failure, transplantation is quite commonly used in treatment. For example, allografts (organ grafts harvested from donors other than the patient him/herself or host/recipient of the graft) of various types, e.g., kidney, heart, lung, liver, bone marrow, pancreas, cornea, small intestine and skin (e.g., epidermal sheets) are currently routinely performed. Xenografts (organ grafts harvested from another species, e.g. non-human animal donors in the case of human recipients), such as porcine heart valves, are also being used clinically to replace their dysfunctional human counterparts. To ensure successful transplantation, it is desirable to obtain the graft from the patient's identical twin or his/her immediate family member to increase histocompatibility (compatibility of genetically defined cellular markers that may be recognized as foreign and attacked by the immune system if mismatched). This is because transplants evoke a variety of immune responses in the host, which results in rejection of the graft by the host immune system, or graft-versus-host disease (hereinafter, referred to as “GVHD”) in which the transplanted immune system cells (bone marrow or hematopoietic cell transplants) cause an attack of host tissues and related and often severe complications.
Bone marrow and/or stem cell transplantation has applications in a wide variety of clinical settings, including solid organ transplantation. A major goal in solid organ transplantation is the engraftment of the donor organ without a graft rejection immune response generated by the recipient, while preserving the immunocompetence of the recipient against other foreign antigens. Typically, nonspecific immunosuppressive agents such as cyclosporin A, azathioprine, corticosteroids including prednisone, and methylprednisolone, cyclophosphamide, and FK506 are used to prevent host rejection responses (Iwasaki, (2004). Clinical Medicine & Research 2(4): 243). They must be administered on a daily basis and if stopped, graft rejection usually results. However, nonspecific immunosuppressive agents function by suppressing all aspects of the immune response, thereby greatly increasing a recipient's susceptibility to infections and diseases, including cancer. Furthermore, although the development of new immunosuppressive drugs has led to an improvement in the survival of patients, these drugs are associated with a high incidence of side effects such as nephrotoxicity and/or hepatotoxicity.
The goal of hematopoietic progenitor cell or stem cell transplantation is to achieve the successful engraftment of donor cells within a recipient host, such that immune and/or hematopoietic chimerism results. Chimerism is the reconstitution of the various compartments of the recipient's hematoimmune system with donor cell populations bearing major histocompatability complex (MHC) molecules derived from both, the allogeneic or xenogeneic donor, and a cell population derived from the recipient or, alternatively, the recipient's hematoimmune system compartments which can be reconstituted with a cell population bearing MHC molecules derived from only the allogeneic or xenogeneic marrow donor. Chimerism may vary from 100% (total replacement by allogenic or xenogeneic cells) to low levels detectable only by molecular methods. Chimerism levels may vary over time and be permanent or temporary.
GVHD is a possible severe or lethal complication of any hematopoietic cell transplant that uses stem cells from either a related or an unrelated donor, which occurs in about 35-50% of recipients of untreated HLA (human leukocyte histocompatibility antigens)-identical marrow grafts (Martin et al., (1985). Blood 66:664-72) and up to 80% of recipients of HLA-mismatched marrow. Such transplants typically are used in the treatment of disorders such as leukemia, bone marrow failure syndromes, and inherited disorders (e.g., sickle cell anemia, thalassemia, immunodeficiency disorders, and metabolic storage diseases such as mucopolysaccharidosis), as well as low-grade lymphoma. GVHD arises from a reaction of donor T cells (T lymphocytes) against MHC or minor histocompatability antigen disparities present on antigen-presenting cells (APC) and various tissues of the individual receiving the donor cells (Schlomchik et al., (1999). Science 285:412-5). GVHD can be exacerbated by tissue injury induced by pre-bone marrow transplant conditioning that includes destruction of the recipient's bone marrow. Acute GVHD (aGVHD) usually occurs within the first three months following a transplant, and can affect the skin, liver, stomach, and/or intestines. Chronic GVHD (cGVHD) is the late form of the disease, and usually develops three months or more after a transplant. The symptoms of cGVHD resemble spontaneously occurring autoimmune disorders such as lupus or scleroderma (Iwasaki, supra).
Therefore, graft rejection still remains a major source of morbidity and mortality in human transplantation and there still exists the need for controlling, reducing, and treating GVHD.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.